Apelqvist G, Wikell C, Carlsson B, Hjorth S, Bergqvist P B, Ahlner J, Bengtsson F
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University, Sweden.
Clin Neuropharmacol. 2000 Nov-Dec;23(6):304-17. doi: 10.1097/00002826-200011000-00003.
Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg x kg(-1) x day(-1)), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCI-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.
慢性肝性脑病（HE）是一种在肝脏受损患者中出现的神经精神综合征。HE患者表现出包括情感障碍在内的各种神经精神症状，因此可能会接受如西酞普兰（CIT）等新型抗抑郁药的治疗。目前，对于慢性HE患者中常用的5-羟色胺选择性抗抑郁药的药代动力学和药效学同时产生的结果还远未明确。因此，我们研究了在有和没有门腔分流术（PCS）的大鼠中，按照体重调整剂量（10mg·kg⁻¹·d⁻¹）进行慢性CIT治疗的效果。监测旷场活动。评估额叶新皮质中的5-羟色胺（5-HT）、5-羟吲哚乙酸（5-HIAA）、去甲肾上腺素（NA）和多巴胺（DA）的输出量。测定血清、脑实质和细胞外液中CIT及其代谢产物去甲西酞普兰（DCIT）和二去甲西酞普兰（DDCIT）的外消旋体水平，包括S-和R-对映体。在所有研究的隔室中，PCS大鼠的CIT水平比接受CIT假治疗的大鼠高（2 - 3倍）。PCS大鼠的DCIT和DDCIT水平也有所升高。在PCS大鼠和对照大鼠之间未检测到S/R比值的主要差异。CIT治疗导致PCS大鼠和对照大鼠之间新皮质输出存在差异，主要在5-HT和DA系统内，但不在NA系统内。对于血清素系统，这种变化在氯化钾去极化刺激后5-HT输出明显升高时得到进一步证实。此外，对PCS大鼠进行CIT治疗显示可“使”5-HT的代谢周转率“正常化”，这表现为5-HIAA水平基础升高的显著降低。CIT治疗使PCS组的行为活动增加或“正常化”。因此，在PCS大鼠中进行等量的慢性CIT治疗会产生对照大鼠中未观察到的药代动力学和药效学变化。这些结果进一步支持了慢性HE状态下5-HT神经传递改变的观点。然而，本研究中对PCS大鼠进行慢性CIT治疗后观察到的初步有益行为反应必须结合观察到的药代动力学和药效学变化来考虑。
